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2012 Grants - Ittner

The Role of Tau in Excitotoxicity in Alzheimer's Disease

Lars M. Ittner, M.D.
The University of Sydney
Sydney, Australia

2012 New Investigator Research Grant

The protein tau normally helps maintain the structure and function of brain cells. Tau is modified by a process called phosphorylation, or the adding of phosphate molecules. But in many neurological disorders, tau becomes excessively modified and loses its ability to carry out its normal functions. This "hyperphosphorylated" tau tends to accumulate into toxic neurofibrillary tangles, which have been shown to hamper cell-to-cell communication in the brain and cause brain cell death. Tangles are one of the hallmarks of the brain changes in Alzheimer's disease. Two of the brain disorders most affected by tau are Alzheimer's disease and frontotemporal dementia.

In earlier studies with Alzheimer's-like mice, Lars M. Ittner, M.D., and colleagues found that tau pathology may help promote another toxic protein in Alzheimer's called beta-amyloid. They observed that by reducing tau levels in their mice, they could prevent beta-amyloid from accumulating into plaques and other harmful clumps. Conversely, overexpression of tau in the rodents' brains increased beta-amyloid accumulation. The researchers also found that tau stimulates abnormal activity in a neurotransmitter (or chemical messenger) called glutamate. This process, in turn, causes the glutamate to produce excessive activity in synapses—the tiny channels through which brain cells communicate with one another. Such overstimulation is known as excitotoxicity, and it leads to brain cell damage and death in early Alzheimer's.

For this proposed study, Dr. Ittner and colleagues will further test their hypothesis that abnormal tau is a causative factor in Alzheimer's-related excitotoxicity. Using their Alzheimer's-like mice, they hope to determine—step by step—how this tau-induced pathology occurs in the brain. They also hope to identify mechanisms that underlie the process, determining how it may involve tau and beta-amyloid interaction, as well as tau-induced gene alterations. In addition, the team will examine links between tau and excitotoxicity in frontotemporal dementia, a disorder that involves tau but not beta-amyloid. Results of this work will shed new light on the role of tau in neurological disease. They could also lead to novel therapies for disease prevention.